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Area of Science:

  • Epigenetics
  • Cancer Biology
  • Polycomb Group Proteins

Background:

  • The BAP1 and ASXL1 proteins form a complex that removes histone H2A monoubiquitin (H2AK119Ub).
  • Mutations in BAP1 and ASXL1 occur in different cancer types, suggesting distinct roles.
  • BAP1 and ASXL1 are crucial for epigenetic regulation and preventing malignant transformation.

Purpose of the Study:

  • To investigate the distinct roles of BAP1 and ASXL1 in epigenetic regulation and cancer.
  • To explore the molecular mechanisms by which BAP1 loss contributes to malignant transformation.
  • To identify potential therapeutic strategies for BAP1-mutant cancers.

Main Methods:

  • Mouse models with conditional Bap1 deletion.
  • Analysis of histone modifications, including H3K27me3 and H4K20me1.
  • In vivo studies involving conditional deletion of Bap1 and Ezh2.
  • Pharmacologic inhibition of EZH2 in mesothelioma cells.

Main Results:

  • Bap1 loss in mice increases H3K27me3, Ezh2 expression, and repression of PRC2 targets.
  • Asxl1 loss leads to reduced H3K27me3, contrasting with Bap1 loss.
  • Conditional deletion of Bap1 and Ezh2 abrogates Bap1 loss-induced myeloid progenitor expansion.
  • BAP1 loss decreases H4K20me1; SETD8 expression reduces EZH2 and proliferation in BAP1-mutant cells.
  • Mesothelioma cells lacking BAP1 are sensitive to EZH2 inhibition.

Conclusions:

  • BAP1 loss promotes epigenetic alterations, including increased H3K27me3 and EZH2 expression, driving myeloid progenitor expansion.
  • H4K20 monomethylation is linked to EZH2 regulation, and its modulation impacts BAP1-mutant cell proliferation.
  • EZH2 pharmacologic inhibition presents a promising therapeutic avenue for BAP1-mutant malignancies.